Project 2. Project Abstract Specific airway epithelial cell proteins can regulate the luminal pH of the airway and of airway glands. For example, airway epithelial and mucous gland pH is affected by luminal bicarbonate transport through the cystic fibrosis (CF) transmembrane regulatory protein (CFTR). Several research groups have found that abnormal airway pH regulation may be relevant to the pathophysiology of CF, asthma and other airway diseases. Further, abnormal airway pH may affect the efficacy of a variety of inhaled treatments, including ?2 agonists. However, evidence to date suggests that not all patients with airways diseases have decreased pH. Further, current diagnostic techniques for identifying decreased airway pH are suboptimal, and the pathophysiological relevance of low airway pH has not been demonstrated in large clinical studies. Our preliminary data and published results suggest that we will be able to develop a reliable, noninvasive clinical test for low airway pH, and to apply that test to the development of personalized therapy. At the very least we want to establish the values and relevance of airway pH in human severe asthma and CF. We propose three Aims in the first cycle of the project that should lead to a new, biomarker-based test and a proof-of concept intervention study, setting the stage for larger scale studies in the second cycle. This project will use all of the cores, and will synergize operationally with Projects 1 and 3. We will begin with an Aim to determine whether our biomarker/challenge tests accurately reflect human lower airway pH in severe asthma. We will then use cell cultures and ex vivo samples from our first Aim to determine the mechanisms by which human airway pH is regulated, and whether these mechanisms can be inform therapy. We will end the first cycle with two clinical studies of the effect of alkaline therapy, directed to patients with low airway pH, to increase albuterol efficacy at baseline a during asthma exacerbations. Numbers from these studies will inform power calculations for larger trials in Cycle 2.